The present invention relates to novel tetrahydropyridines, to a method for the preparation thereof and to the pharmaceutical compositions containing them.
WO92/07831 describes tetrahydropyridines substituted with a benzofuran-6-yl alkyl group carrying a triple bond in the alkyl chain, having dopaminergic activity.
It has now been found that certain tetrahydropyridines, substituted with a benzofuryl alkyl radical or benzothienyl alkyl radical, have powerful activity with respect to the modulation of TNF-alpha (from Tumour Necrosis Factor).
TNF-alpha is a cytokine which has recently provoked interest as a mediator of immunity, of inflammation, of cell proliferation, of fibrosis, etc. There is a very high concentration of this mediator in inflamed synovial tissue and it exercises an important role in the pathogenesis of autoimmunity (Annu. Rep. Med. Chem., 1997, 32:241-250).
Thus, according to one of its aspects, the present invention relates to tetrahydropyridines of formula (I): 
in which
R1 represents a hydrogen or halogen atom, or a group CF3;
R2 and R3 represent, independently, a hydrogen atom or a methyl group;
n and nxe2x80x2 each represent, independently, 0 or 1;
* represents the positions of attachment;
A represents N or CH;
X represents a sulfur or oxygen atom;
R4 and R5 represent, independently, a hydrogen atom or a (C1-C6) alkyl group;
and their salts or solvates.
In the present description, the term xe2x80x9c(C1-C6) alkylxe2x80x9d denotes a monovalent radical comprising a straight- or branched-chain saturated C1-C6 hydrocarbon.
In the present description, the term xe2x80x9chalogenxe2x80x9d denotes an atom chosen from chlorine, bromine, iodine and fluorine.
Preferred compounds are those in which n is zero.
Other preferred compounds are those in which R1 is in position 3 of the benzene.
Other preferred compounds are those in which R1 is a group CF3.
Other preferred compounds are those in which R2 and R3 are each a hydrogen atom.
Other preferred compounds are those in which R4 and R5 are each a methyl group.
The salts of the compounds of formula (I) according to the present invention comprise both the addition salts with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., and the addition salts which allow suitable separation or crystallization of the compounds of formula (I), such as picrate, oxalate or the addition salts with these optically active acids, for example camphosulfonic acids and mandelic or substituted mandelic acids.
The stereoisomers which are optically pure, and also the mixtures of isomers of the compounds of formula (I), due to the asymmetric carbon, when one of R2 and R3 is a methyl and the other a hydrogen, in any proportion, are part of the present invention.
The compounds of formula (I) can be synthesized using a method which envisions
(a) reacting the compound of formula (II): 
xe2x80x83in which A and R1 are defined as above, with a functional derivative of the acid of formula (III): 
xe2x80x83in which R2, R3, R4, R5, n and X are as defined above,
(b) reducing the carbonyl group of the compound of formula (IV): 
(c) dehydrating the intermediate piperidinol of formula (V): 
(d) isolating the compound of formula (I) thus obtained and, optionally, transforming it into one of its salts or solvates, or its N-oxide (nxe2x80x2=1 in formula I).
As a suitable functional derivative of the acid of formula (III), use may be made of the free acid, optionally activated (for example with BOP=benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), an anhydride, a mixed anhydride, an active ester or an acid halide, preferably bromide. Among the active esters, the p-nitrophenyl ester is particularly preferred, but the methoxyphenyl, trityl and benzhydryl esters and similar esters are also suitable.
The reaction of step (a) can be suitably carried out in an organic solvent at a temperature of between xe2x88x9210xc2x0 C. and the reflux temperature of the reaction mixture.
It may be preferable to carry out the reaction under cold conditions when it is exothermic, as when chloride is used as the functional derivative of the acid of formula (III).
As the reaction solvent, use is preferably made of a halogen-based solvent, such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, but also of other organic solvents compatible with the reagents used, for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane, may also be used.
The reaction may be suitably carried out in the presence of a proton acceptor, for example of an alkali metal carbonate or of a tertiary amine such as triethylamine.
The reduction of step (b) can be suitably carried out with suitable reducing agents, such as borane complexes, for example borane dimethyl sulfide ([CH3]2Sxe2x80x94BH3), aluminum hydrides or a complex hydride of lithium and aluminum, in an inert organic solvent at a temperature of between 0xc2x0 C. and the reflux temperature of the reaction mixture according to usual techniques.
The term xe2x80x9cinert organic solventxe2x80x9d is intended to mean a solvent which does not interfere with the reaction. Such solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane.
According to a preferential embodiment, the procedure is carried out with borane dimethyl sulfide used in excess relative to the starting compound (II), at the reflux temperature, optionally under inert atmosphere. The reduction is normally terminated after a few hours.
The dehydration of step (c) is easily carried out, for example, using an acetic acid/sulfuric acid mixture, at a temperature of between ambient temperature and the reflux temperature of the solvent used, or using para-toluenesulfonic acid in an organic solvent, such as, for example, benzene, toluene or chlorobenzene.
The compounds of formula (I) may also be prepared by condensation of a tetrahydropyridine of formula (VI): 
in which A and R1 are as defined above, with a compound of formula (VII): 
in which R2, R3, R4, R5, n and X are as defined above and Q is a leaving group, isolation of the compound of formula (I) thus obtained and optional transformation into one of its salts or solvates, or its N-oxide.
As leaving group Q, use may be made, for example, of a halogen atom or any group which can be condensed with an amine. The condensation reaction is carried out conventionally by mixing the starting compounds (VI) and (VII) in an organic solvent such as an alcohol, for example methanol or butanol, in the presence of a base such as an alkali metal carbonate, at a temperature of between ambient temperature and the reflux temperature of the solvent chosen.
The desired compound is isolated according to conventional techniques in the form of a free base or of one of its salts. The free base may be transformed into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate or acetone, or a hydrocarbon such as hexane. It may be transformed into N-oxide by oxidation according to conventional methods, for example with 3-chloroperbenzoic acid.
The starting compounds of formulae (II), (III), (VI) and (VII) are known or else they may be prepared in a similar way to the known compounds.
The compounds of the invention have properties which are advantageous with respect to the inhibition of TNF-xcex1.
These properties were demonstrated using a test aimed at measuring the effect of molecules on TNF-xcex1 synthesis induced in Balb/c mice by lipopolysaccharide (LPS) of Escherichia Coli (055:B5, Sigma, St Louis, Mo.).
The products to be tested are administered orally to groups of 5 female 7- to 8-week-old Balb/c mice (Charles River, France). One hour later, the LPS is administered intravenously (10 xcexcg/mouse). A blood sample is taken from each animal 1.5 hours after administration of the LPS. The samples are centrifuged and the plasma is recovered and frozen at xe2x88x9280xc2x0 C. The TNF-xcex1 is measured using commercial kits (R and D, Abingdon, UK).
In this test, compounds representative of the invention proved to be very active, inhibiting TNF-xcex1 synthesis even at very low doses.
Due to this activity, and to their low toxicity, the compounds of formula (I) and its salts or solvates may indeed be used in the treatment of diseases related to immune and inflammatory disorders. In particular, the compounds of formula (I) may be used to treat atherosclerosis, autoimmune diseases, diseases which lead to the demyelinization of neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption, osteoporosis, Paget""s disease, multiple myeloma, uveoretinitis, septic shock, septicemia, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn""s disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, lupus erythematosus disseminatus, hemodynamic shock, ischemic pathological conditions (myocardial infarction, myocardial ischemia, coronary vasospasm, angina, cardiac insufficiency, heart attack), postischemic reperfusion injuries, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpes virus), AIDS-related opportunistic infections, tuberculosis, psoriasis, atopic and contact dermatosis, diabetes, cachexia, cancer and radiation-mediated damage.
The compounds of formula (I) and their pharmaceutically acceptable salts and solvents are administered orally or parenterally, preferably orally.
In the pharmaceutical compositions of the present invention orally, the active principle may be administered in unit administration forms, as a mixture with conventional pharmaceutical carriers, to animals and humans for treating the abovementioned disorders. The suitable unit administration forms comprise, for example, tablets, optionally scored, gelatin capsules, powders, granules and oral solutions or suspensions.
When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets may be coated with sucrose or other suitable materials, or they may be treated such that they have prolonged or delayed activity and that they continuously release a predetermined amount of active principle.
A preparation of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, and also a flavoring and a suitable colorant.
The water-dispersible powders or granules can contain the active ingredient as a mixture with dispersing or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavor enhancers.
The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
The amount of active principle to be administered depends, as always, on the degree of progression of the disease and also on the age and weight of the patient. Nevertheless, the unit doses generally comprise from 0.001 to 100 mg, better still from 0.01 to 50 mg, preferably from 0.1 to 20 mg, of active principle, advantageously from 0.5 to 10 mg.
According to another of its aspects, the present invention relates to a combination comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and at least one compound chosen from immunosuppressants, such as interferon beta-1b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors, methatrexate.
More particularly, the invention relates to a combination comprising a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and at least one compound chosen from roquinimex (1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-3-quinolinecarboxanilide), myloran (product from the company Autoimmune containing bovine myelin), antegren (monoclonal human antibody from Elan/Athena Neurosciences) and recombinant interferon xcex2-1b.
Other possible combinations are those consisting of a compound of formula (I), or one of its pharmaceutically acceptable salts or solvates, and a potassium-channel blocker such as, for example, fampridine (4-aminopyridine).
According to another of its aspects, the invention relates to a method for treating diseases related to immune and inflammatory disorders, in particular atherosclerosis, autoimmune diseases, diseases which lead to the demyelinization of neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption, osteoporosis, Paget""s disease, multiple myeloma, uveoretinitis, septic shock, septicemia, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn""s disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, lupus erythematosus disseminatus, hemodynamic shock, ischemic pathological conditions (myocardial infarction, myocardial ischemia, coronary vasospasm, angina, cardiac insufficiency, heart attack), postischemic reperfusion injuries, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpes virus), AIDS-related opportunistic infections, tuberculosis, psoriasis, atopic and contact dermatosis, diabetes, cachexia, cancer and radiation-mediated damage, comprising the administration of a compound of formula (I), or of one of its pharmaceutically acceptable salts or solvates, alone or in combination with other active principles.
The following examples illustrate the invention.